JPS5855145B2 - It's hard to believe, it's so weird - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to nitrogen-containing heterocyclic compounds having pharmacological activity, pharmaceutical compositions comprising the compounds, and methods for producing them.

Although the compounds of the present invention can also exist as addition salts, for convenience, the sharp compounds are described herein.

It has been believed that many physiologically active substances bind to specific sites known as receptors during their action in the animal body.

Although histamine is thought to be a compound that acts in this way, it is thought that there is more than one type of histamine receptor because the effects of histamine can be divided into more than one type.

The type of action of histamine that is commonly blocked by drugs called "antihistamines" (typically mepyramine) is thought to include receptors designated H-i.

Recently, Black et al.
ture, 1972, vol. 236, p. 385)
Another group of substances described by , ) is characterized by acting at histamine receptors other than the H-1 receptor, and this other receptor has been designated the H-2 receptor.

Certain of this group of substances are relevant to the present invention and are useful for inhibiting certain effects of histamine that are not inhibited by the "antihistamines" described above.

The substances of the invention are also useful in inhibiting certain effects of gastrin.

In this specification, the term "lower alkyl" has 1 to 1 carbon atoms.
4 means an alkyl group.

The compounds of the present invention are represented by the following general formula; [wherein A is a pyrimidone ring (optionally substituted with 1 to 2 lower alkyl or aralkyl) together with the carbon atom and ring nitrogen atom shown in the formula] ), forming a thiopyrimidone ring, imidacilline ring (optionally substituted with 1 to 2 lower alkyl or aralkyl), pyridone ring, quinolone ring, quinazolinone ring or doriazinone ring (optionally substituted with lower alkyl) Z
means a group represented by sulfur or methylene group; n means 2] Since the formed ring structure may form a tautomer, the formula [■] only one of the expressions
It should be understood that this is merely an illustration of one.

Of particular importance among the compounds falling within the scope of formula CI) are the compounds of the following formulas [III) to [■]: [wherein R has the same meaning as the above formula [■]; is oxygen or sulfur; Yl and Y2 are the same or different and may be hydrogen, lower alkyl or aralkyl or Y and Y2 together with adjacent carbon atoms may form a phenyl ring; Y3 and Y4 are the same or different and are hydrogen, lower alkyl or aralkyl] Particularly useful compounds are: 2-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-4-pyrimidone, 2-(2-(4-
Methyl-5-imidazolylmethylthio)ethylaminoco-5-ethyl-6-methyl-4-pyrimidone, 2-C2
-(4-Methyl-5-imidazolylmethylthio)ethylaminoco-5-benzyl-6-methyl 4-pyrimidone and 2-(2-(4-methyl-5-imidazolylmethylthio)ethylamino)-(no-pyrido-4- on.

Compounds of the present invention are of the formula [wherein A' together with the above A or a carbon atom and a ring nitrogen atom in the formula form a lower alkoxy-substituted pyridine ring or a lower alkoxy-substituted quinoline ring; Q is a halogen, thiol or methylthio. A'
A compound in which is a lower alphkytetrasubstituted pyridine ring or a lower alkoxy-substituted quinoline ring can be converted into the corresponding pyridone or quinolone compound, and if desired, the obtained pyrimidone compound can be changed into the corresponding thiopyrimidone compound, or if desired, the obtained pyrimidone compound can be changed into the corresponding thiopyrimidone compound. It is produced by converting a thiopyrimidone compound into the corresponding pyrimidone compound.

Methods for the preparation of compounds of formula RNH2 are described in our UK Patents Nos. 1,305,547 and 1,338,169.

As mentioned above, the compound represented by the formula [■] has pharmacological activity as an antagonist in the animal body against certain effects of histamine that cannot be prevented by "antihistamines" such as mepyramine. I discovered that.

For example, the compound was found to selectively inhibit histamine-stimulated gastric acid secretion from the perfused stomach of urethane-anesthetized rats.

Similarly, the compounds are often used in the Black et al.
It showed an antagonistic effect on the action of histamine on other tissues, which is the H-2 receptor, according to a report by Lack et al.

Examples of such tissues include isolated perfused guinea pig heart, isolated guinea pig right atrium, and isolated rat uterus.

It has also been found that the compound inhibits gastric acid secretion stimulated by pentagastrin or food.

The active concentration of the composition comprising the compound is within the effective dosage range of 2 to 256 micromoles/kg for intravenous administration to the anesthetized rat described above.

Many of the compounds produce 50% inhibition in this test at doses of 5-20 micromoles/kg.

For therapeutic purposes, the pharmacologically active compound is usually used in a pharmaceutical composition comprising at least one or more of the compound or a pharmaceutically acceptable acid addition salt thereof as an essential active ingredient, together with a pharmaceutical carrier. Administered as

Such acid addition salts include hydrochloric, hydrobromic, hydroiodic, sulfuric and maleic acid groups.

The pharmaceutical carrier used may be solid or liquid; examples of solid carriers include lactose, china clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.

Examples of liquid carriers are cilantro, fallen oil, olive oil, water, and the like.

A variety of dosage forms may be used, and if solid carriers are used, they may be prepared as tablets, powders or granules in hard gelatin capsules, or troches or lozenges.

The amount of solid carrier varies widely, but preferably about 25
771! 1;' to about 11.

If liquid carriers are used, they may be prepared as sterile injectable solutions such as tablets, emulsions, soft gelatin capsules, ampoules, or suspensions in aqueous or non-aqueous liquids.

The pharmaceutical compositions are prepared in conventional manner including methods such as mixing, granulating and compressing, or dissolving the ingredients appropriate to the desired preparation.

The amount of active ingredient in the composition is an amount effective to inhibit the effects of histamine and may be administered orally or parenterally.

Preferably, each dosage unit contains about 50 In
9 to about 250 ■, most preferably about 100 to about 20
It is 0m9.

Preferably, the same dosage of the active ingredient is 1 to 1 per day.
Administer 3 times.

The daily dose is preferably about 150 mI; ~about 75
0 m9, most preferably about 300 to 600 m.

In some cases, other pharmacologically active compounds may be included in the composition.

Advantageously, the composition is in a dosage unit form suitable for the desired method of administration, such as, for example, an ill, a capsule, an injection or a cream for topical use.

The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino-4-pyrimidone dihydrochloride 2.61 of 4(5)=(2-aminoethyl)thiomethyl-5(4)-methyl imidazole and 1,49 2-
A homogeneous mixture of methylthio-4-pyrimidone was heated at 150°C.
Heat for at least 30 minutes at 150-160 °C for 2 minutes.
Heat for an hour.

After cooling, the reaction mixture is triturated with water to obtain the crude salt.

This is filtered off and dissolved in 5N hydrochloric acid.

Evaporate to dryness and recrystallize the residue from aqueous ethanol.
2,1y of 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino)-4-pyrimidone dihydrochloride is obtained.

Melting point: 246-248°C (elemental analysis, measured value: C139,
25; H, 5,2; N120.4; S, 9.6;
Calculated value as C1,20,5, C11H1□Cl2N50s: C,39,1; H,5,1;N120.7;S
, 9.5; C1,20,9,5) The melting point of the purified salt obtained by recrystallizing the initial crude salt from ethanol/water is 219-2.
2FC0 Example 2 2-(2-(4-Methyl-5-imidazolylmethylthio)ethylaminoco-6-methyl-4-pyrimidone dihydrochloride was prepared by the method of Example 1 above, 4(5) of 4.5? 2
-aminoethyl)thiomethyl)-5(4-methylimidazole with 2.7'fI of 6-methyl-2methylthio-4
-Reacted with pyrimidone to produce 2(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-6-methyl-
4-pyrimidone dihydrochloride is obtained.

Melting point: 247-250'C (crystallized from ethanol.

Elemental analysis, actual value: C141,1; N15.7; N,1
9.8; S, 8.9; C1, 19,8, Cl2H1
, Cl2N50S Calculated value: C140,9;H,
5,4;N, 19.9;C1,20,1) Example
3 2-(2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-dimethyl 4-pyrimidone 2
Hydrochloride 4(5)(2-
2.61 of 5,6-dimethyl 2-methylthio-4-aminoethyl)thiomethyl-5(4)methylimidazole
Reaction with pyrimidone yields 2-(2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-simethyl-4-pyrimidone dihydrochloride.

Melting point: 235-237°C (crystallized from methanol.

Elemental analysis, actual value: C142.8; N16.0; N,
18.7; S, 8.6; C1゜■8.8
Calculated value as C13H2, Cl2N50S: C14
2,6; N15.8; N, 19.1; S, 8
．． 75 ; C1,19,4) Example 4 2-(4-(4-imidazolyl)butylaminoco-4-pyrimidone dihydrochloride 2-(5)(4-
Reacting aminobutyl)imidazole with 1.41 of 2-methylthio-4-pyrimidone yields 2(4-(4-imidazolyl)butylaminoco4-pyrimidone dihydrochloride.

Melting point: 215-222°C (crystallized from ethanol.

Elemental analysis, actual value: C143.15; N15.6; N,
22.5. ;C1,22,8,C7□H1□C1□N5
Calculated value as 0: C143,15; N15.6; N,
22.9; C1,23,2) Example 5 4-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-thiopyrimidone dihydrochloride 7.41 parts of 4 (5) -C (2-7
A solution of minoethyl)thiomethyl)-5(4)-methylimidazole and the 2,4-dimercaptopyrimidine of 4.11 is heated at reflux temperature for 12 hours.

After cooling, separate the precipitated oil by decantation and
Wash three times with Qml of water and dissolve in 2N hydrochloric acid.

The solution is evaporated to dryness and the residue is recrystallized from ethanol to give 4-C2-(4-methy)L/-5-imidazolylmethylthio)ethylaminoco2-thiopyrimidone dihydrochloride.

Melting point: 254-257°C (elemental analysis, measured value: C137,
2; H, 4, 9; N, 19.7; S, 18.
Calculated value as 0°C1, H17C12N5S2: C13
7,3; H, 4,8; N119.8; S, 18
．． 1) Example 6 4-C2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-pyrimidone 1.0 in 5 ml of water
A solution of 4-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-thiopyrimidone dihydrochloride and 0.35? of chloroacetic acid) was heated on a steam bath for 4 hours.
Heat for 0 minutes.

Then, 8 ml of concentrated hydrochloric acid was added, and the solution was heated at reflux temperature for 2 hours.
After heating for an hour, it is evaporated to dryness.

The oily residue was dissolved in 5 ml of water, made basic with ammonium hydroxide, and the resulting precipitate was washed with hot water to give 4-[2(4
-Methyl-5-imidazolylmethylthio)ethylaminoco-2-pyrimidone is obtained.

Melting point 249-251'C (elemental analysis, actual value: C149
, 5; H, 5, 6; N126.3; S, 18.0
, C1, Calculated value as N15N50S: C149,8;
N15.7; N, 26.4; S, 18.1
) Example 7 2-C2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-imidacillin 4-one dihydrochloride 3.4 ?ノ4(5) =(2
=aminoethyl)thiomethyl-5-(4)-methylimidazole and 2.61 of 2-methylthi-2-imidacylin-4-one hydroiodide are left at room temperature for 4 days.

The crude product is filtered off, dissolved in dilute hydrochloric acid and made basic with aqueous potassium carbonate to give 2-[2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-imidacillin-4-one.

Melting point 224-225°C (decomposed). Dissolved in dilute hydrochloric acid, evaporated to dryness and recrystallized from aqueous ethanol to give the dihydrochloride.

Melting point: 226-228°C (decomposition.

Elemental analysis, actual value: C131,1; H, 5,4; N,
21.45; S, 9.7; C1,21,6,C
Calculated value as l0HI 7 C12N50s: C1
36,8; N15.25; N, 21.5; S, 9.8;
C1,21,7) Example 8 2-(2-(4-methyl)-5-imidazolylmethylthio)ethylamino)-4(IH)-quinazolinone 2.6r of 4(5)-(2-aminoethyl) thiomethyl-5(4)-methylimidazole and 1.91 of 2-
A homogeneous mixture of methylthio-4(IH)-quinazolinone was reacted at 120° C. for 4.5 hours to obtain the crude salt of 2.7Z,
This was acidified with hydrochloric acid in the same manner as in Example 1, recrystallized from ethanol/ether, and 2-(2-(4
-Methyl-5-imidazolylmethylthio)ethylamino]
4. Obtain (IH)-quinazolinone dihydrochloride.

Melting point 249-252°C (elemental analysis, measured value: C145
,8;H,4,9;N117.8;S18゜],C1
Calculated value as 5H14C12N50S: C146,4
;N14.9;N,18.0;S,8.3) Example 9 2-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-6-n-propyl 4-pyrimidone of Example 1) 2(2-(4- Methyl-5-imidazolylmethylthio)ethylaminoco-6-n-propyl-4
- Obtaining the hygroscopic dihydrochloride of pyrimidone.

Melting point 125-130°C (crystallized from butanol/ether.

Elemental analysis, actual value: C144.3; N16.2; N, 1
8.3; S, 8.2; C1, 18,7, C14
Calculated value as H23C12N50S: C144,2;
N16.1; N, 18.4; S, 8.4
;C1,18,6) Example 10 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino)-5-ethyl-6methyl-4-pyrimidone dihydrochloride By the method of Example 1 above, 2 .02 of 4 (5) (2-
Reacting aminoethyl)thiomethyl-5(4)methylimidazole with 1.46P of 5-ethyl-6methyl-2-methylthio-4-pyrimidone yields 2-C2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-5. −
Ethyl-6methyl-4-pyrimidone dihydrochloride is obtained.

Melting point: 203-207°C (crystallized from Improper Tool).

Elemental analysis, actual value: C143,6; N16,1; N,1
7.9; S, 8.0; C1,18,5,C1
Calculated value as 4H23CI2N506: C144,2;
H, 6,1; N, 18.5; S, 8.4;
C1,18,6) Example 11 2-C2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-5-methyl-2imidacyline-4-
[on], a solution of 151 of 5-methyl-2-thiohydantoin and 16.3'if of methyl iodide in 30 rnl of dry ethanol is heated at reflux temperature for 1.5 h and then left overnight at 0 °C. .

The crystalline product was filtered off and washed with ether to yield 17.8'i
! 2-Methylthio-5-methyl-2-imidacillin-
The hydroiodide salt of 4-one is obtained.

Hydroiodide 2.71.2.51 4(5)(2-
A solution of aminoethyl)thiomethyl-5(4-)methylimidazole and triethylamine of 11 in 20 rrll of dry ethanol is left at room temperature for 10 days.

The resulting crude product (1,6P, melting point 218°C) was dissolved in hydrochloric acid, made basic with a saturated aqueous potassium carbonate solution, and 2-[2
-(4-Methyl5-imidazolylmethylthio)ethylamine A hydrate of io5-methylimidacillin-4-one is obtained.

Melting point: 216-220°C (elemental analysis, measured value: C, 48,
5; N16.4; N125.4; S, 11.
9, C1□H17N50S Calculated value as %H20: C
148,3; H, 6,5; N, 25.6; S, 1
1.7) Example 12 5,5-dimethyl-2-C2-(4-methyl5-imidazolylmethylthio)ethylaminoco2-imidacillin-
4-on by the method of Example 11 above, 14.4? 5゜5-dimethyl-2-thiohydantoin to 2-methylthio-5.
Change to 5-dimethyl-2-imidacylin-4-one hydroiodide (17,4P, melting point 187-189°C).

This hydroiodide 5.7Te and 6.85P 4(5
A solution of )-(2-aminoethyl)thiomethyl-5(4)-methylimidazole in 4.5 ml of dry ethanol is left at room temperature for 4 days.

The reaction mixture was evaporated to dryness and the residue was recrystallized from water to give 5
・5-dimethyl-2(2-(4-methyl-5-imidazolylmethylthio)ethylamine]-2-imidacillin-
4-one (3,11) is obtained.

Melting point 232-236°C. Furthermore, it is recrystallized from water to obtain an analytical sample.

Melting point: 235-237°C (elemental analysis, measured value: C150,
9;H, 6,9;N124.8;S, 11.4,
”12 Calculated value as H19N50S: C151,2;
N16.8; N, 24.9; S, 11.4) Example 13 5-benzyl-2-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-2-imidacyline-
4-one Following the method of Example 11 above, 5-benzyl 2-thiohydantoin is converted to 2-methylthio-5-benzyl-2-imidacylin-4-one hydroiodide (melting point 19
2-194°C).

This hydroiodide 2,5z, 1.91 of 4(5)(2
-aminoethyl)thiomethyl-5(4)-methylimidazole and 0.74P triethylamine at 15rI
The solution in 1 ml of dry ethanol is left at room temperature for 4 days.

The reaction mixture was evaporated to dryness, the residue was dissolved in 25 TLl of Improper Tools, the solution was poured into 200 ml of ether and 1.231 of 5-benzyl-2-(2-(4
-Methyl-5-imidazolylmethylthio)ethylaminoco2-imidacillin-4-one is obtained.

Melting point 104-107°C0 Example 14 2-(2-(4-Methyl-5-imidazolylmethylthio)ethylaminocopyrimido-4-thione dihydrochloride 51 of 2-1:2-( 4
Methyl-5-imidazolylmethylthio)ethylamine]
A mixture of -4-pyrimidone and 41 phosphorus pentasulfide is heated at reflux temperature for 2 hours with stirring.

The reaction mixture is evaporated to dryness, boiled with water for 30 minutes and evaporated again to dryness.

The residue is dissolved in rehydrated ammonium oxide, washed with chloroform and the aqueous layer is evaporated to dryness.

Concentrated hydrochloric acid was added to the residue to obtain a pale yellow solid, which was dissolved in warm water, filtered, and the filtrate was acidified with concentrated hydrochloric acid to give 2-[2(4
-Methyl-5-imidazolylmethylthio)ethylaminocopyrimido-4-thione dihydrochloride is obtained.

Melting point 245-247°C (elemental analysis, actual value: C, 37
,0;H,4,9;N, 19. '55; S.

Calculated value as 17,7, C1□H1□Cl2N5S2:
C137,3; H,4,8; N119.8; S118
．． 1) Example 15 2-C2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(IH)-pyrid6-one 20 4(5)-(2-aminoethyl)thiomethyl-
5(4)-methylimidazole and 11.9f of 2-
The mixture of Furomo 6-ethoxypyridine is heated at 160° C. for 4 hours with stirring.

After cooling, the reaction mixture is dissolved in 20% aqueous hydrobromic acid and extracted with ether to recover the unchanged 2-bromo-6-ethoxypyridine.

The aqueous layer is made basic with potassium carbonate, extracted with chloroform, the extracts are combined, washed with water, and dried over magnesium sulfate.

After removing the chloroform, the residue was chromatographed on silica gel, eluting first with ethyl acetate to remove impurities and then with ethyl acetate-methanol-chloroform (4:1:2) to obtain the required product. get something

The eluate was evaporated to give an oily 2-ethoxy-6-C2-(4
-Methyl-5-imidazolylmethylthio)ethylaminocopyridine is obtained which is treated with an ethanolic solution of picric acid to obtain dipicrate.

Melting point: 172°C This ethoxypyridine salt 3.4'f? 100771
A solution of 1 in 5N hydrochloric acid is heated at reflux temperature for 2.5 hours.

The reaction mixture is evaporated to dryness, the residue is dissolved in a little water and the solution is made basic with aqueous potassium carbonate solution.

Wash once with chloroform and leave at 0°C overnight.

2-C2-(4-methyl-5imidazolylmethylthio)
The crystals of ethylamino](IH)-pyrid-6-one are collected and recrystallized from water to obtain the pure product.

Melting point 85°C (elemental analysis, actual value: C154,25; N1
6.0; N, 20.9; S, 11,9, Cl2H16N
Calculated value as 40S: C, 54, 5; H, 6, 1; N
121.2; S.

12.1) Example 16 2-C2-(4-methyl-5-imidazolylmethylthio)ethylamino, l-(IH)-pyrid4-one 7.6r of 4(5)-(2-aminoethyl)thiomethyl -5(4)-methylimidazole and 3.81 2-
The mixture of bromo-4-pyridone was heated to 160°C with stirring.
Heat for 3 hours.

After cooling, the reaction mixture was chromatographed on silica gel, first with ethyl acetate-isopropanol (5:
1) to remove unreacted 2-bromo-4-pyridone, and elute the product with isopropanol-ethanol (5:1).

After combining the eluates and evaporating, the residue was evaporated using IRA400 (OH type).
ion exchange chromatography using a resin, first eluting with water to remove unchanged amines, then IN
Further purification is achieved by eluting the product with hydrochloric acid.

The acidic fraction was evaporated and the residue was recrystallized from infropanol-ethyl acetate to give 2-[2-(4methyl-5-
imidazolylmethylthio)ethylamino)-(IH)-
Pyrid-4-one is obtained.

Melting point 208-210'C Example 17 3-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-6-methyl-1,2,4-triazin-(2H)-5-one 7.64P of 3 -Methylthio-
6-Methyl-1,2,4-triazon-5-one and 8.75 P of 5-(2-aminoethyl)thiomethyl-
The homogeneous mixture of 4-methylimidazole is slowly heated to 160°C and this temperature is maintained for 1 hour.

After cooling, the resulting solid was dissolved in 100 ml of 2N hydrochloric acid,
Filter and make the filtrate basic with aqueous potassium carbonate solution.

The resulting precipitate is collected, washed with water, dried and extracted with methanol using a Soxhlet extractor for 16 hours.

Cool the methanol solution to obtain pale yellow crystals.

Recrystallized from dimethyl sulfoxide to obtain 3-C of 7.81
2-(4-Methyl-5-imidazolylmethylthio)ethylamino-6-methyl-2,4-triazine-(2H
)-5-one is obtained.

Melting point: 264-266°C (decomposition. Elemental analysis, measured value: C1
46,8; H, 5,7; N, 29.9; 5112.
Calculated value as 0, C1, N16N60S: C147,1
;H, 5,7;N, 30.0;3. 11.44)
Example 18 3-C2-(4-methyl-5-imidazolylmethylthio)ethylamino]-1,2,4-triazine-(2H)
-5-one 8.6r 5-(2-aminoethyl)thiomethine=4
- A homogeneous mixture of methylimidazole and 6.61' 3-methylthio-1,2,4-triazin-2H-5one is slowly heated to 120°C and this temperature is maintained for 1 hour.

After cooling, the resulting solid was recrystallized twice from n-propanol and twice from water to give 3-C2-(5-methyl-4=imidazolylmethylthio)ethylamino]-1,2,4~
Triazin-(2H)-5-one is obtained.

Melting point: 238-238.5°C (elemental analysis, measured value: C14
5,1; N15.55; N, 31.5; S, 1
1.9, calculated value as C1oH14N60S: C145
, 1; N15.3; N131.6; S, 12
．． 0) Example 19 2-C2-(4-Methyl-5-imidazolylmethylthio)ethylaminoco-5-benzyl-6methyl-4-pyrimidone 60 g of 5-benzyl-6-methylthiouracil and 1.06? of sodium hydroxide is dissolved in 30 WLl of water.

The solution is cooled and 60 ml of ethanol and 3.67 P of methyl iodide are added while stirring.

The mixture is heated and cooled at 60° C. for 0.5 hours, and the resulting solids are collected and washed with water.

The filtrate was acidified to pH 4 with acetic acid to obtain a secondary precipitate, which was recrystallized from ethanol to give a product of 5.53? 5-benzyl-6-methyl-2-methyl-4-pyrimidone is obtained.

Melting point 220-221.5℃ 1.28? A homogeneous mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole and 1.84P of 5benzyl-6-methyl-2-methylthio-4piIJ midone was heated at 150-160
Heat in an oil bath at C for 4.5 hours.

The mixture was cooled, washed with water and recrystallized from Improper Tools to 1.82? 2-(:2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-5-
Benzyl-6-methyl-4-pyrimidone is obtained.

Melting point 140-141.5°C (elemental analysis, measured value: C1
61,7; N16.6; N, l 8,5; S, 8
．． Calculated value as 20, C1, H23N50S: C161
, 8; N16.3; N, l 8.95; S,
8.68) Example 20 2-(2-(4-methyl-5-imidazolylmethylthio)ethylaminoco-4-quinolone 3.72P of 2-chloro-4-ethoxyquinoline and 3.1 of 5-(2-
(aminoethyl)thiomethyl-4-methylimidazole are heated together in an oil bath at 150-160°C for 3 hours.

Cool, wash the residue with water and dry.

Column chromatography (silica gel column,
2-[2-(4-methyl-
5-imidazolylmethylthio)ethylamino-2-4-ethokifuquinoline is obtained.

Melting point 152.5-153.5°C (elemental analysis, measured value: C
, 63, 2; H.

6.5; N, 16.1; S, 9.1, Cl8H22N4
Calculated value as 0S: C, 63, 1; H, 6, 5; N, 1
6.4; S, 9.4) 1.691 of 2-(2-(4-methyl-5-imidazolylmethylthio)ethylamino-4-ethoxyquinoline and 30 ml of concentrated hydrochloric acid are refluxed together for 17 hours.

The solution is evaporated to dryness and the residue is dissolved in water and made basic with potassium carbonate.

The oily precipitate was separated by tectonation, washed with water, and crystallized from impropanol-water to give 2-[2(4-
Methyl-5-imidazolylmethylthio)ethylamine io-4-quinolone is obtained.

Melting point 121-124℃ (elemental analysis, actual value: C160,
1;H.

5.7;N, 17.1;S, 9.9,C
Calculated value as 16H18N40S: C161,1;H
,5,8;N,17.8;S,102) Example 21 4-4:4-(4-imidazolyl)butylaminoco-2
~Thiopyrimidone 2.82 of 4(5)(4-
Aminobutyl)imidazole was reacted with 144P dimercaptopyrimidine to form 4-[4(4-imidazolyl)
Butylamino)-2-f opyrimidone is obtained.

Melting point 209-211'C (crystallized from npropertool.

Elemental analysis, actual value: C151.4; N16.3; N1
27.0; S, ■3.0, C11H15N5S0・
Calculated value as 4H20: C151,6; H,6,3;
N127.35; S, 12.5) Example 22 Formulation 2-C2-(4-Methyl-5-imida 150■Zolylmethylthio)ethylaminoco4-pyrimidone sucrose 75rn9 The blended ingredients are passed through a sieve and filled into a cell.

Example 23 Mix hard gelatin cuff 2-(2-(4-methyl-5-imida 200■Zolylmethylthio)ethylaminoco5-benzyl-6-methyl-4-pyrimidone lactose 00719) Pass the blended ingredients through a sieve and mix. and fill it into the cell.

hard gelatin cuff

Claims (1)

[Scope of Claims] A compound represented by formula 1 [wherein A has the same meaning as below; Q means halogen, thiol or alkylthio] is represented by formula RNH2 (wherein R has the same meaning as below) [In the formula, A is a carbon atom and a ring nitrogen atom together with the carbon atom and ring nitrogen atom shown in the formula, Pyrimidone ring (optionally substituted with 1-2 lower alkyl or aralkyl), thiopyrimide 4, imitabrinone ring (optionally substituted with 1-2 lower alkyl or aralkyl), pyridone ring, quinolone ring , forming a quinazolinone ring or a doriazinone ring (optionally substituted with lower alkyl); R is the formula %
) (wherein, Het is imidazole (optionally substituted with lower alkyl): Z is sulfur or methylene group; n is 2
A method for producing a nitrogen-containing complex ring compound or a pharmaceutically acceptable addition salt thereof. A compound represented by the formula 2 [wherein A' forms a lower alkoxy-substituted pyridine ring or a lower alkoxy-substituted quinoline ring together with the carbon atom and ring nitrogen atom in the formula; Q means halogen, thiol or alkylthio]. RNH
2 (wherein R has the same meaning as below), the product is then converted into the corresponding pyridone or quinolone compound, and, if desired, the obtained compound is converted into a pharmaceutically acceptable compound. [In the formula, A forms a pyridone ring or a quinolone ring together with the carbon atom and ring nitrogen atom shown in the formula; R is the formula (wherein, Het is imidazole (lower alkyl); (may be substituted); z is sulfur or methylene group; n is 2
A method for producing a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable addition salt thereof. [In the formula, A' forms a pyrimidone ring together with the carbon atom and ring nitrogen atom shown in the formula; Q means halogen, thiol or alkylthio]. Same meaning) is reacted with an amino compound represented by the formula [In the formula, A' has the same meaning as Punishment, R
is the same meaning as below], reacts it with phosphorus pentasulfide to convert it into the corresponding thiopyrimidone compound, and optionally converts the obtained compound into a pharmaceutically acceptable addition salt. [wherein A forms a thiopyrimidone ring together with the carbon atom and ring nitrogen atom shown in the formula; R is the formula %] (wherein, Het is imidazole (optionally substituted with lower alkyl) ); z is sulfur or methylene group; n is 2
A method for producing a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable addition salt thereof.